Steps towards a practical synthesis of macrocyclic bisbenzylisoquinolines

Yusuf M. Al-Hiari, Stephen J. Bennett, Brian Cox, Robert J. Davies, Abedawn I. Khalaf, Roger D. Waigh, Alan J. Worsley

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Tetrahydrooxathiadiazapentacene I is prepd. as a potential intermediate for the prepn. of bisbenzylisoquinoline macrocycles, using a sulfur atom as a 'stitch' to restrict the conformations and reactivity of intermediates. Coupling of p-cresol and p-bromotoluene to yield bis(p-tolyl) ether followed by sulfuration, oxidn., and bromination yields the brominated phenoxathiins II (R = Br2CH, BrCH2; R1 = Br2Ch, BrCH2, Me). II (R = R1 = Br2CH) undergoes silver nitrate-mediated hydrolysis, condensation with nitromethane, and redn. of the bis(nitroethenyl)dioxophenoxathiin with diisobutylaluminum hydride to yield bis(aminoethyl)phenoxathiin III; III is also prepd. by substitution of II (R = R1 = BrCH2) with potassium cyanide and redn. of the nitrile moieties with diisobutylaluminum hydride. Formylation of III and Bischler-Napieralski cyclocondensation yields I in addn. to two minor regioisomers. Using either addn. reactions of benzylmagnesium chlorides to I or redn. of I to an octahydrooxathiadiazapentacene followed by acylation, regioselective lithiation and alkylation with benzylic chlorides, complex mixts. contg. the desired dibenzyloxathiadiazapentacenes are obtained. Alkylation reactions of benzyl halides with acyltetrahydroisoquinolines and addn. reactions of benzylic Grignard reagents to dihydroisoquinolines are performed. A bis(pivaloyldihydroisoquinolinylmethyl)phenyl ether IV is prepd. from N-pivaloyl-1,2,3,4-tetrahydroisoquinoline and 4-[3-(bromomethyl)phenoxy]benzyl bromide (V) (prepd. in three steps from 4-bromobenzaldehyde and 3-hydroxybenzaldehyde); attempts to couple V to an octahydrooxathiadiazapentacene by lithiation and alkylation fail.
Original languageUndefined/Unknown
Pages (from-to)647-659
Number of pages13
JournalJournal of Heterocyclic Chemistry
Volume42
Issue number4
DOIs
Publication statusPublished - 2005

Keywords

  • macrocyclic bisbenzylisoquinolines
  • heterocyclic chemistry

Cite this

Al-Hiari, Y. M., Bennett, S. J., Cox, B., Davies, R. J., Khalaf, A. I., Waigh, R. D., & Worsley, A. J. (2005). Steps towards a practical synthesis of macrocyclic bisbenzylisoquinolines. Journal of Heterocyclic Chemistry, 42(4), 647-659. https://doi.org/10.1002/jhet.5570420426
Al-Hiari, Yusuf M. ; Bennett, Stephen J. ; Cox, Brian ; Davies, Robert J. ; Khalaf, Abedawn I. ; Waigh, Roger D. ; Worsley, Alan J. / Steps towards a practical synthesis of macrocyclic bisbenzylisoquinolines. In: Journal of Heterocyclic Chemistry. 2005 ; Vol. 42, No. 4. pp. 647-659.
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title = "Steps towards a practical synthesis of macrocyclic bisbenzylisoquinolines",
abstract = "Tetrahydrooxathiadiazapentacene I is prepd. as a potential intermediate for the prepn. of bisbenzylisoquinoline macrocycles, using a sulfur atom as a 'stitch' to restrict the conformations and reactivity of intermediates. Coupling of p-cresol and p-bromotoluene to yield bis(p-tolyl) ether followed by sulfuration, oxidn., and bromination yields the brominated phenoxathiins II (R = Br2CH, BrCH2; R1 = Br2Ch, BrCH2, Me). II (R = R1 = Br2CH) undergoes silver nitrate-mediated hydrolysis, condensation with nitromethane, and redn. of the bis(nitroethenyl)dioxophenoxathiin with diisobutylaluminum hydride to yield bis(aminoethyl)phenoxathiin III; III is also prepd. by substitution of II (R = R1 = BrCH2) with potassium cyanide and redn. of the nitrile moieties with diisobutylaluminum hydride. Formylation of III and Bischler-Napieralski cyclocondensation yields I in addn. to two minor regioisomers. Using either addn. reactions of benzylmagnesium chlorides to I or redn. of I to an octahydrooxathiadiazapentacene followed by acylation, regioselective lithiation and alkylation with benzylic chlorides, complex mixts. contg. the desired dibenzyloxathiadiazapentacenes are obtained. Alkylation reactions of benzyl halides with acyltetrahydroisoquinolines and addn. reactions of benzylic Grignard reagents to dihydroisoquinolines are performed. A bis(pivaloyldihydroisoquinolinylmethyl)phenyl ether IV is prepd. from N-pivaloyl-1,2,3,4-tetrahydroisoquinoline and 4-[3-(bromomethyl)phenoxy]benzyl bromide (V) (prepd. in three steps from 4-bromobenzaldehyde and 3-hydroxybenzaldehyde); attempts to couple V to an octahydrooxathiadiazapentacene by lithiation and alkylation fail.",
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Al-Hiari, YM, Bennett, SJ, Cox, B, Davies, RJ, Khalaf, AI, Waigh, RD & Worsley, AJ 2005, 'Steps towards a practical synthesis of macrocyclic bisbenzylisoquinolines', Journal of Heterocyclic Chemistry, vol. 42, no. 4, pp. 647-659. https://doi.org/10.1002/jhet.5570420426

Steps towards a practical synthesis of macrocyclic bisbenzylisoquinolines. / Al-Hiari, Yusuf M.; Bennett, Stephen J.; Cox, Brian; Davies, Robert J.; Khalaf, Abedawn I.; Waigh, Roger D.; Worsley, Alan J.

In: Journal of Heterocyclic Chemistry, Vol. 42, No. 4, 2005, p. 647-659.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Steps towards a practical synthesis of macrocyclic bisbenzylisoquinolines

AU - Al-Hiari, Yusuf M.

AU - Bennett, Stephen J.

AU - Cox, Brian

AU - Davies, Robert J.

AU - Khalaf, Abedawn I.

AU - Waigh, Roger D.

AU - Worsley, Alan J.

PY - 2005

Y1 - 2005

N2 - Tetrahydrooxathiadiazapentacene I is prepd. as a potential intermediate for the prepn. of bisbenzylisoquinoline macrocycles, using a sulfur atom as a 'stitch' to restrict the conformations and reactivity of intermediates. Coupling of p-cresol and p-bromotoluene to yield bis(p-tolyl) ether followed by sulfuration, oxidn., and bromination yields the brominated phenoxathiins II (R = Br2CH, BrCH2; R1 = Br2Ch, BrCH2, Me). II (R = R1 = Br2CH) undergoes silver nitrate-mediated hydrolysis, condensation with nitromethane, and redn. of the bis(nitroethenyl)dioxophenoxathiin with diisobutylaluminum hydride to yield bis(aminoethyl)phenoxathiin III; III is also prepd. by substitution of II (R = R1 = BrCH2) with potassium cyanide and redn. of the nitrile moieties with diisobutylaluminum hydride. Formylation of III and Bischler-Napieralski cyclocondensation yields I in addn. to two minor regioisomers. Using either addn. reactions of benzylmagnesium chlorides to I or redn. of I to an octahydrooxathiadiazapentacene followed by acylation, regioselective lithiation and alkylation with benzylic chlorides, complex mixts. contg. the desired dibenzyloxathiadiazapentacenes are obtained. Alkylation reactions of benzyl halides with acyltetrahydroisoquinolines and addn. reactions of benzylic Grignard reagents to dihydroisoquinolines are performed. A bis(pivaloyldihydroisoquinolinylmethyl)phenyl ether IV is prepd. from N-pivaloyl-1,2,3,4-tetrahydroisoquinoline and 4-[3-(bromomethyl)phenoxy]benzyl bromide (V) (prepd. in three steps from 4-bromobenzaldehyde and 3-hydroxybenzaldehyde); attempts to couple V to an octahydrooxathiadiazapentacene by lithiation and alkylation fail.

AB - Tetrahydrooxathiadiazapentacene I is prepd. as a potential intermediate for the prepn. of bisbenzylisoquinoline macrocycles, using a sulfur atom as a 'stitch' to restrict the conformations and reactivity of intermediates. Coupling of p-cresol and p-bromotoluene to yield bis(p-tolyl) ether followed by sulfuration, oxidn., and bromination yields the brominated phenoxathiins II (R = Br2CH, BrCH2; R1 = Br2Ch, BrCH2, Me). II (R = R1 = Br2CH) undergoes silver nitrate-mediated hydrolysis, condensation with nitromethane, and redn. of the bis(nitroethenyl)dioxophenoxathiin with diisobutylaluminum hydride to yield bis(aminoethyl)phenoxathiin III; III is also prepd. by substitution of II (R = R1 = BrCH2) with potassium cyanide and redn. of the nitrile moieties with diisobutylaluminum hydride. Formylation of III and Bischler-Napieralski cyclocondensation yields I in addn. to two minor regioisomers. Using either addn. reactions of benzylmagnesium chlorides to I or redn. of I to an octahydrooxathiadiazapentacene followed by acylation, regioselective lithiation and alkylation with benzylic chlorides, complex mixts. contg. the desired dibenzyloxathiadiazapentacenes are obtained. Alkylation reactions of benzyl halides with acyltetrahydroisoquinolines and addn. reactions of benzylic Grignard reagents to dihydroisoquinolines are performed. A bis(pivaloyldihydroisoquinolinylmethyl)phenyl ether IV is prepd. from N-pivaloyl-1,2,3,4-tetrahydroisoquinoline and 4-[3-(bromomethyl)phenoxy]benzyl bromide (V) (prepd. in three steps from 4-bromobenzaldehyde and 3-hydroxybenzaldehyde); attempts to couple V to an octahydrooxathiadiazapentacene by lithiation and alkylation fail.

KW - macrocyclic bisbenzylisoquinolines

KW - heterocyclic chemistry

U2 - 10.1002/jhet.5570420426

DO - 10.1002/jhet.5570420426

M3 - Article

VL - 42

SP - 647

EP - 659

JO - Journal of Heterocyclic Chemistry

JF - Journal of Heterocyclic Chemistry

SN - 0022-152X

IS - 4

ER -